Our multidisciplinary team (with expertise in hepatology, gastroenterology, biochemistry, pathology, pharmacology, nutrition, immunology, microbiology, and anatomy) will continue studies on the metabolism and metabolic effects of ethanol and the mechanisms of medical disorders associated with chronic ethanol consumption. We will assess the role of gastrointestinal ADH, characterize the ethanol specific cytochrome P450 and elucidate the importance of the microsomal ethanol oxidizing system (MEOS) in primates. We will study abnormalities in hepatic aldehyde dehydrogenase activity and acetaldehyde metabolism, including its possible role in the pathogenesis of the fetal alcohol syndrome (through microtubular alterations and chromosomal abnormalities). We will assess the pathologic implications of alterations in gut flora and other mechanisms of liver injury, including effects of oxygen radicals, lipid peroxidation and disturbances in fatty acids and prostaglandin. Abnormalities in collagen synthesis and breakdown will be investigated and the response of cultured myofibroblasts and Ito cells to agents that affect collagen production will be evaluated. We plan to assess biochemical differences between alcoholics and nonalcoholics and to apply these findings to the validation of blood tests to detect heavy drinking and alcohol induced liver damage. Using our baboon model of cirrhosis as a guide, we will define precirrhotic lesions and corresponding blood changes which might allow us to recognize, at an early stage, alcoholics prone to develop cirrhosis, thereby enhancing our effectiveness in the prevention of this irreversible and potentially lethal complication. Attempts at treatment will involve agents that may counteract liver injury, including assessment of the effectiveness of hepatitis B vaccination in our alcoholic population. Alcohol-nutrition interactions will be evaluated, with emphasis on the pathogenesis of alcohol-induced pancreatic lesions, vitamin A deficiency, as well as toxicity and elucidation of a new microsomal pathway of retinol metabolism using, in part, deermice lacking alcohol dehydrogenase. The carcinogenic role of alcohol, the diagnosis of alcohol induced precancerous lesions and their prevention by beta-carotene will be studied in animal models and in alcoholics. Our ultimate goal is the application of newly acquired knowledge to the successful prevention and treatment of alcohol related diseases by permitting early diagnosis and by replacing current symptomatic therapy with rational and hopefully more effective approaches.